5. Summary of Data Reported and Evaluation

5.1 Exposure data

Silica (silicon dioxide) occurs in crystalline and amorphous forms.
Of the several crystalline polymorphs of silica found in nature,
quartz is by far the most common, being abundant in most rock
types, notably granites, sandstones, quartzites and in sands and
soils. Cristobalite and tridymite are found in volcanic rocks.
Because of the wide usage of quartz-containing materials, workers
may be exposed to quartz in a large variety of industries and
occupations. Respirable quartz levels exceeding 0.1 mg/m3 are
most frequently found in metal, non-metal and coal mines and mills;
in granite quarrying and processing, crushed stone and related
industries; in foundries; in the ceramics industry; in construction
and in sandblasting operations. Cristobalite is formed from quartz
or any other form of silica at high temperatures (> 1400 oC)
and from some amorphous silicas (e.g. diatomaceous earth) at somewhat
lower temperatures (800 oC). Cristobalite exposure is notably associated
with the use and calcination of diatomaceous earth as well as
refractory material installation and repair operations. Few data
exist on non-occupational exposures to crystalline silica. It
has been estimated that respirable crystalline silica levels in
the low mg/m3 range are common in ambient air. Exposure may also
occur during the use of a variety of consumer or hobby products.

Amorphous silica is found in nature as biogenic silica and as
silica glass of volcanic origin. One form of biogenic silica,
diatomaceous earth, originates from the skeletons of diatoms deposited
on sea floors and contains small amounts of cristobalite and quartz.
After calcination (which significantly increases the cristobalite
content), diatomaceous earth is used as a filtration agent, carrier
for pesticides, filler in paints and paper and as a refractory
or abrasive product in a variety of industries. Occupational exposure
to both amorphous and crystalline silica may occur during the
production and use of diatomaceous earth. Fibres of amorphous
silica are produced by a variety of plants, such as sugar cane
and rice, and may be inhaled when released into the air during
farming operations.

Large quantities of synthetic amorphous silica are produced as
pyrogenic (fumed) silicas and wet process silicas (precipitated
silicas and silica gels) which are used, notably, for reinforcing
elastomers, for thickening resins, paints and toothpaste, and
as free-flow additives. Exposure to synthetic amorphous silica
may occur during its production and use. Synthetic amorphous silica
may also be ingested as a minor constituent (< 2%) of a variety
of food products where it serves as an anti-caking agent, and
as an excipient in some pharmaceutical preparations. Silica fume
is a form of amorphous silica (with small amounts of crystalline
silica) unintentionally released into the air from certain metallurgical
processes.

The mechanical, thermal and chemical history of a silica particle
determines its surface properties and presence and abundance of
various surface functionalities. Surface reactivity varies among
silica samples from different sources. Heating converts hydrophilic
surfaces into hydrophobic ones. In particular, freshly fractured
surfaces are more reactive than aged ones.

5.2 Human carcinogenicity data

The evaluations for both crystalline and amorphous silica pertain
to inhalation resulting from workplace exposures. Lung cancer
was the primary focus. The Working Group's evaluation of the epidemiological
evidence for potential causal relations between silica and cancer
risk was focused principally on findings from studies that were
least likely to have been distorted by confounding and selection
biases. Among these studies, those that addressed exposure-response
associations were especially influential in the Working Group's
deliberations.

Crystalline silica

Possible differences in carcinogenic potential among polymorphs
of crystalline silica were considered. Some studies were of populations
exposed principally to quartz. In only one study (that of United
States diatomaceous earth workers) was the exposure predominantly
cristobalite. Studies of mixed environments (i.e. ceramics, pottery,
refractory brick) could not delineate exposures specifically to
quartz or cristobalite. Although there were some indications that
cancer risks varied by type of industry and process in a manner
suggestive of polymorph-specific hazards, the Working Group could
only reach a single evaluation for quartz and cristobalite. Nonetheless,
the Working Group did note a reasonable degree of consistency
across studies of workers exposed to one or both polymorphs.

Ore mining

Seventeen cohort and five case-control studies were reported on
ore miners potentially exposed to silica dust. The majority of
these studies reported an elevated mortality for lung cancer among
silica-exposed workers. However, in only a few ore mining studies
were confounders such as other known occupational respiratory
carcinogens taken into account. In such studies consistent evidence
for a silica-lung cancer relationship was not found. Noteworthy
instances where a relationship between lung cancer and crystalline
silica was not detected include two independent studies of gold
miners in South Dakota, United States, a study of miners in one
lead and one zinc mine in Sardinia, Italy, and a study of tungsten
miners in China. The results of most of the other studies could
not be interpreted as an independent effect of silica - workers
were concomitantly exposed to either radon, arsenic, or both,
and in some cases other known or suspected occupational respiratory
carcinogens were present in the work environment (e.g. diesel
exhaust, polycyclic aromatic hydrocarbons, cadmium). In a few
studies, no information was provided on exposure to radon or arsenic,
in spite of the likelihood of these exposures.

Quarries and granite works

Six cohort studies were available for review. These studies provide
important information on cancer risks because the workplace environments
were generally free of reported exposures to potentially confounding
agents (e.g., radon). All studies revealed lung cancer excesses.
Direct quantification of silica dust exposure concentrations in
relation to lung cancer risk was not conducted in any of these
studies, mainly due to sparse occupational hygiene measurement
data. However, some studies provided indications of exposure-response
associations when surrogate dose data, such as duration of employment
and category of exposure, were used. For example, findings for
lung cancer include a nearly twofold mortality elevation among
long-term granite shed workers in Vermont, United States, an eightfold
elevation among sandstone workers in Copenhagen, Denmark, and
a relative risk of roughly 3.5 among crushed granite stone workers
in the United States with long duration of exposure and time since
exposure onset. One study of German slate quarry workers indicated
a more prominent relationship between employment duration and
lung cancer among workers with silicosis than among workers without
silicosis. The Working Group regarded radiographic evidence of
silicosis as a marker of high exposure to silica.

Ceramics, pottery, refractory brick and diatomaceous earth
industries

In refractory brick and diatomaceous earth plants, the raw materials
(amorphous or crystalline silica) are processed at temperatures
around 1000 oC with varying degrees of conversion to cristobalite.
The results of two cohort studies of refractory brick workers
from China and Italy and of one cohort study of diatomaceous earth
workers from the USA provided consistent evidence of increased
lung cancer with overall relative risks of about 1.5. In the study
of refractory brick workers from China, a modest increasing trend
of lung cancer was found with radiographic profusion category.
A nearly twofold elevated lung cancer risk was found among long-term
workers in the Italian study. In the study of United States diatomaceous
earth workers, increasing exposure-response gradients were detected
for both non-malignant respiratory disease and lung cancer mortality.

In ceramic and pottery manufacturing plants, exposures are mainly
to quartz, but where high temperatures are used in ovens, potential
exposures to cristobalite may occur. In a cohort study of British
pottery workers, lung cancer mortality was slightly elevated;
a nested case-control analysis of lung cancer did not show an
association with duration of exposure, but indicated a relationship
between lung cancer mortality and average and peak exposures in
firing and post-firing operations, with relative risks of approximately
2.0. In an Italian case-control study, apart from a fourfold increase
in lung cancer in registered silicotics, there was a small increase
in lung cancer for subjects without silicosis. In a case-control
study from the Netherlands, there was little relationship overall
between work in ceramics and lung cancer risk, but there was some
suggestion that lung cancer risk was related to cumulative exposure.

Foundry workers

There were only three large cohort studies of foundry workers
where silica dust or silicosis were considered as risk factors
for cancer. One study from Denmark found a slightly elevated risk
of lung cancer in silicotics compared with non-silicotics. Two
studies, one from the United States and one from China, yielded
conflicting results for lung cancer. The Chinese study suggested
positive associations of silica with both lung cancer and stomach
cancer, although there remained a potential for confounding by
exposures to polycyclic aromatic hydrocarbons. The United States
study did not demonstrate an association of lung cancer with cumulative
silica exposure.

Silicotics

The vast majority of studies on registered silicotics reported
excess lung cancer risks, with relative risks ranging from 1.5
to 6.0. Excesses were seen across countries, industries and time
periods. A number of studies reported exposure-response gradients,
using varying indicators of exposure. Some studies, in particular
one from North Carolina (USA) and one from Finland, provide reasonable
evidence for an unconfounded association between silicosis and
lung cancer risk.

Summary of findings for crystalline silica (quartz and cristobalite)

For the evaluation of crystalline silica, the following studies
provided the least confounded examinations of an association between
silica exposure and cancer risk: (1) South Dakota, United States, gold miners; (2) Danish stone
industry workers; (3) Vermont, United States, granite shed and
quarry workers; (4) United States crushed stone industry workers;
(5) United States diatomaceous earth industry workers; (6) Chinese
refractory brick workers; (7) Italian refractory brick workers;
(8) United Kingdom pottery workers; (9) Chinese pottery workers;
(10) cohorts of registered silicotics from North Carolina, United
States and Finland. Not all of these studies demonstrated excess
cancer risks. However, in view of the relatively large number
of epidemiological studies that have been undertaken and, given
the wide range of populations and exposure circumstances studied,
some non-uniformity of results would be expected. In some studies,
increasing risk gradients have been observed in relation to dose
surrogates - cumulative exposure, duration of exposure or the
presence of radiographically defined silicosis - and, in one instance,
to peak intensity exposure. For these reasons, the Working Group
therefore concluded that overall the epidemiological findings
support increased lung cancer risks from inhaled crystalline silica
(quartz and cristobalite) resulting from occupational exposure.
The observed associations could not be explained by confounding
or other biases.

Amorphous silica

Very little epidemiological evidence was available to the Working
Group. No association was detected for mesothelioma with biogenic
amorphous silica fibres in the three community-based case-control
studies. Separate analyses were not performed for cancer risks
among a subset of diatomaceous earth industry workers exposed
predominantly to amorphous silica.

5.3 Animal carcinogenicity data

Various forms and preparations of crystalline silica were tested
for carcinogenicity by different routes of exposure.

Different specimens of quartz with particle sizes in the respirable
range were tested in four experiments in rats by inhalation and
in four experiments in rats by intratracheal instillation. In
these eight experiments, there were significant increases in the
incidence of adenocarcinomas and squamous-cell carcinomas of the
lung; marked, dense pulmonary fibrosis was an important part of
the biological response.

Pulmonary granulomatous inflammation and slight to moderate fibrosis
of the alveolar septa but no pulmonary tumours were observed in
hamsters in three experiments using repeated intratracheal instillation
of quartz dusts.

No increase in the incidence of lung tumours was seen with one
sample of quartz in the strain A mouse lung adenoma assay and
with another quartz sample in a limited inhalation study in mice.
Silicotic granulomas and lymphoid cuffing around airways but no
fibrosis were seen in the lungs of quartz-treated mice.

In several studies in rats using single intrapleural or intraperitoneal
injection of suspensions of several types of quartz, thoracic
and abdominal malignant lymphomas, primarily of the histiocytic
type (MLHT) were found. In rats, intrapleural injection of cristobalite
and tridymite with particles in the respirable range resulted
in malignant lymphomas, primarily MLHT.

A pronounced positive interactive effect of one sample of quartz
and Thorotrast (an a-radiation emitting material) on pulmonary
carcinogenesis was observed in one inhalation study in rats. Enhancement
of benzo[a]pyrene-induced respiratory tract carcinogenesis
by two different samples of quartz was seen in one intratracheal
instillation study in hamsters.

In two studies in hamsters given mixtures of quartz and ferric
oxide (1 : 1) by intratracheal instillation, no pulmonary tumours
were observed.

Diatomaceous earth was tested by oral administration in rats and
by subcutaneous and intraperitoneal injection in mice. No increase
in the incidence of tumours was found after oral and subcutaneous
administration; after intraperitoneal injection, a slightly increased
incidence of intra-abdominal lymphosarcomas was reported.

In one test by intrapleural injection of biogenic silica fibres
to rats, the silica fibres were not found to influence the tumour
response to crocidolite but a small number of pleural mesotheliomas
was reported in animals injected with 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one
followed by administration of the biogenic silica fibres.

A food-grade micronized synthetic amorphous silica was tested
by oral administration to mice and rats. No increased incidence
of tumours was seen. In one study in rats using intrapleural implantation
of two different preparations of synthetic amorphous silica, no
increased incidence of tumours was observed.

5.4 Other relevant data

Crystalline silica

Crystalline silica deposited in the lungs causes epithelial and
macrophage injury and activation. Crystalline silica translocates
to the interstitium and the regional lymph nodes. Crystalline
silica results in inflammatory cell recruitment in a dose-dependent
manner. Neutrophil recruitment is florid in rats exposed to high
concentrations of quartz; marked, persistent inflammation occurs
accompanied by proliferative responses of the epithelium and interstitial
cells. In humans, a large fraction of crystalline silica persists
in the lungs, culminating in the development of chronic silicosis,
emphysema, obstructive airways disease and lymph node fibrosis
in some studies. In-vitro studies have shown that crystalline
silica can stimulate release of cytokines and growth factors from
macrophages and epithelial cells; evidence exists that these events
occur in vivo and contribute to disease. Crystalline silica
stimulates release of reactive oxygen and nitrogen intermediates
from a variety of cell types in vitro. Oxidative stress
is detectable in the lungs of rats following exposure to quartz.

Much less is known about the acute lung responses to inhaled crystalline
silica in humans. Subjects with silicosis show an inflammatory
response characterized by increased macrophages and lymphocytes
but minimal increases in neutrophil numbers.

Only one human study was available on subjects exposed to dust
containing crystalline silica, with no indication of the level
of exposure; it showed an increase in the levels of sister chromatid
exchange and chromosomal aberrations in peripheral blood lymphocytes.

Most cellular genotoxicity assays with crystalline silica have
been performed with quartz samples. Some studies gave positive
results, but most were negative. Some quartz samples induced micronuclei
in Syrian hamster embryo cells, Chinese hamster lung V79 cells
and human embryonic lung Hel 299 cells, but not chromosomal aberrations
in the same cell types. Two quartz samples induced morphological
transformation in Syrian hamster embryo cells in vitro
and 5 quartz samples induced transformation in BALB/c-3T3 cells.
While quartz did not induce micronuclei in mice in vivo,
epithelial cells from the lungs of rats intratracheally exposed
to quartz showed hprt gene mutations. Inflammatory cells
from the quartz-exposed rat lungs caused mutations in epithelial
cells in vitro. Direct treatment of epithelial cells in
vitro with quartz did not cause hprt mutation.

Tridymite was tested in only one study, where it induced sister
chromatid exchange in co-cultures of human lymphocytes and monocytes.

Increasing in-vitro and in-vivo evidence suggests that the rat
lung tumour response to crystalline silica exposure is a result
of marked and persistent inflammation and epithelial proliferation.
Other pathways such as a role for crystalline silica surface-generated
oxidants or a direct genotoxic effect are not ruled out; however,
at present, there is no convincing evidence for these alternative
pathways.

Amorphous silica

Amorphous silicas have been studied less than crystalline silicas.
They are generally less toxic than crystalline silica and are
cleared more rapidly from the lung.

Biogenic silica fibres induced ornithine decarboxylase activity
of epidermal cells in mice following topical application. No data
were available to the Working Group on the genotoxicity of other
amorphous silica particles.

5.5 Evaluation

There is sufficient evidence in humans for the carcinogenicity
of inhaled crystalline silica in the form of quartz or cristobalite
from occupational sources

There is inadequate evidence in humans for the carcinogenicity
of amorphous silica.

There is sufficient evidence in experimental animals for
the carcinogenicity of quartz and cristobalite.

There is limited evidence in experimental animals for the
carcinogenicity of tridymite.

There is inadequate evidence in experimental animals for
the carcinogenicity of uncalcined diatomaceous earth.

There is inadequate evidence in experimental animals for
the carcinogenicity of synthetic amorphous silica.

Overall evaluation

In making the overall evaluation, the Working Group noted that
carcinogenicity in humans was not detected in all industrial circumstances
studied. Carcinogenicity may be dependent on inherent characteristics
of the crystalline silica or on external factors affecting its
biological activity or distribution of its polymorphs.

Crystalline silica inhaled in the form of quartz or cristobalite
from occupational sources is carcinogenic to humans (Group
1).

Amorphous silica is not classifiable as to its carcinogenicity
to humans (Group 3).